Journal of Human Hypertension (2007) 21, 594–597 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh COMMENTARY Stroke, with or with no ice? Observations on amphetamine for the management of acute stroke CV Borlongan and DC Hess Department of Neurology, Medical College of Georgia and Medical Research Service, VA Medical Center, Augusta, GA, USA Journal of Human Hypertension (2007) 21, 594–597; doi:10.1038/sj.jhh.1002206; published online 19 April 2007 Known as the club drug and as a robust performance among its personnel in World War II to assist them to enhancer around the world, amphetamine (alpha- remain attentive and vigilant. Anecdotal accounts of methyl-phenethylamine) is a central nervous system Adolf Hitler, who displayed Parkinson-like symp- stimulant that has become a mainstream prescrip- tom in his latter years, reveal his personal physician tion drug to treat narcolepsy and attention-deficit administered him daily intravenous injections of hyperactivity disorder (ADHD). Amphetamine is the methamphetamine as a treatment for depression and parent compound of a broad range of psychoactive fatigue. In contemporary military operations, the US derivatives, such as 3,4-methylenedioxymetham- military and even NASA have previously used phetamine (MDMA) (Ecstasy) and methampheta- amphetamines to retard fatigue in their troops and mine. Originally available as racemic salt sulphate astronauts. with equal amounts of levo- and dextro-isoform, the Despite their medical use, illicit production and current predominant form of the drug is dextroam- diversion of amphetamines and methamphetamines phetamine sulphate (also called dexamphetamine or have led to classification of these drugs as controlled D-amphetamine) consisting entirely of the D-isomer. substances with high potential for drug addition, Laboratory evidence indicates that D-amphetamine which is a major problem in world societies.2 and L-amphetamine act preferentially on the dopa- Nonetheless, when the drugs are used within the minergic system and norepinephrinergic, respec- recommended doses, the drug’s addictive, as well as tively, but the main reinforcing and behavioural- other physical (e.g., obsession to perform repetitive stimulant effects of amphetamine are correlated tasks, decreased appetite, increased sexual re- with enhanced dopaminergic activity, primarily in sponse, and fatigue and depression following the the mesolimbic dopaminergic system.1 excitement stage) and psychological (e.g., hallucina- The methylation of amphetamine renders the tions, mental states resembling schizophrenia, loss substance more lipid soluble, thereby facilitating its of REM sleep) side effects, can be greatly reduced. transport across the blood–brain barrier and enhan- To this end, although such use remains experimen- cing its psychostimulatory effects. Its N-methylated tal, novel clinical indications of D-amphetamine analog methamphetamine, popularly referred to as include reduction of fatigue in cancer patients3 and crystal meth or ice, has been prescribed as the as an antidepressant for HIV patients with depres- centrally active D-isomer of methamphetamine or D- sion and debilitating fatigue.4 Most recently, methamphetamine to control narcolepsy, ADHD, and D-amphetamine has been proposed as a therapeutic extreme obesity, whereas the other isoform L- agent for stroke. methamphetamine, a potent sympathetic nervous The concept of using D-amphetamine, or amphe- system trigger (i.e., increasing heart rate and blood tamines in general, for treating stroke, although only pressure), is available as an the over-the-counter drug recently gaining considerable attention, has a long Vicks inhaler for nasal decongestant. history. In 1977, Bloom and co-workers treated Classic examples of amphetamine and metham- stroke animals with the antidepressant desmethyli- phetamine use include the distribution of metham- mipramine (commonly known as desipramine), phetamine-laced chocolates by the German military which inhibits the reuptake of norepinephrine, and found that the focal cortical infarction-induced hyperactivity was blocked.5 This observation chal- Correspondence: Professor CV Borlongan, Department of Neuro- lenged the prevailing concept at that time (and logy, Medical College of Georgia and Medical Research Service, VA Medical Center, Augusta, GA 30912, USA. maybe some in the field still hold this view even E-mail: [email protected] now) that while stroke presents with an apparent Published online 19 April 2007 local injury producing deficits via a point-to-point Amphetamine for the management of acute stroke CV Borlongan and DC Hess 595 brain structure-behavioural function mechanism, tent across these laboratory studies is that the assessment and subsequent treatment interven- D-amphetamine is shown to enhance recovery when tion of these stroke symptoms will benefit from the drug is paired with lesion-specific training or considering the ‘gestalt brain’ approach. That is, sensory stimulation, paving the way to introduce stroke symptoms of apathy and depression may pharmacologic enhancement of recovery after focal correspond to emotional alterations resulting from brain injury as a justified treatment regimen for pathophysiological processes in catecholamine (i.e., stroke patients undergoing physical therapy. norepinephrine) neurons that are remotely located Since the initial pilot clinical study in 1988, at away from the site of the stroke injury. Of note, least a dozen clinical trials have been conducted to norepinephrine and amphetamine are both phe- date. Walker-Batson et al.12 studied 10 hemiplegic nethylamine, with intraventricular infusion of nor- patients with stroke onset between 16 and 30 days, epinephrine replicating the effect of amphetamine.6 and used 10 doses of 10 mg dexamphetamine at Accordingly, the desipramine action on norepi- 4-day intervals, with the doses again combined with nephrine, albeit amphetamine, seen by Bloom and physical therapy. Significant improvement in the co-workers may be considered the first laboratory rate and extent of motor recovery in the treatment investigation designed to alter the amphetamine group was recognized as early as 1 week after levels in the stroke brain as a therapeutic strategy. completion of D-amphetamine therapy, which was Eleven years, however, would pass since the maintained up to at least 12 months. In response to milestone desipramine study before D-amphetamine the concern that the drug may be toxic, Walker- would be directly tested in stroke patients. A Batson et al. conducted a follow-up study on a larger double-blind pilot study was performed on a small patient pool, within 16–42 days of stroke onset, and cohort of patients with established cerebral infarc- treated 28 patients with D-amphetamine and 16 tion.7 The study was designed to evaluate the effect patients with placebo 30 min before physiotherapy of amphetamine on recovery of motor function. Four session on an alternating cycle of every third/fourth stroke patients received amphetamine, while the day for 10 sessions.13 The data revealed that the drug other four patients were given placebo within 3–10 was well tolerated during the 12-month course of days of ischaemic stroke onset. Amphetamine or the study. A parallel study by the same group placebo was combined with a session of physical revealed that such D-amphetamine paired with therapy, and patients were evaluated in their motor physical therapy accelerates recovery of stroke performance using the Fugl–Meyer scale. Patients patients from aphasia.14 In a more recent study, D- treated with amphetamine exhibited higher motor amphetamine alone increased language learning of scores than the placebo-treated patients, suggesting artificial vocabulary in healthy subjects.15 that amphetamine improved the clinical outcome of Partly because age is a risk factor of stroke, Sonde the stroke rehabilitation therapy. The small subject et al.16 performed a clinical study similar to Walker- population and the acute treatment protocol (single Batson et al., but enrolled 39 elderly subjects within dose of amphetamine and one session of physical 5–10 days of a new stroke-related hemiparesis. In therapy) and short testing study period are some addition, doses of D,L-amphetamine were given concerns raised in this study. Moreover, the authors 60 min before physiotherapy. Unfortunately, sub- conceded that the observed effect varied among jects with intracerebral haemorrhage were included individual patients, with some patients displaying in this study. More troubling is that some patients remarkable improvement of motor ability, while were discharged to complete the trial medication at others exhibiting only modest recovery. An equally home. Not surprisingly, this study resulted in critical confounding variable in this study is that amphetamine combined with physiotherapy not post-stroke depression is common, and the stroke promoting motor recovery or functional capacity in patients’ difficulties in conforming with physical stroke patients. Sonde and Lokk17 also recently rehabilitation maybe due to their concomitant performed a randomized, double-blind, placebo- depression. Therefore, effectively treating the de- controlled clinical trial and demonstrated that D- pression in stroke patients, such as with the use of amphetamine while safe and effective did not exert D-amphetamine with known antidepressant effects, added benefit than the placebo-treated patients could have mediated the observed